Abstract Dermcidin (DCD) is a candidate oncogene localized at 12q13.1. It is produced by benign melanocytic naevi and dark cells of eccrine sweat glands and proteolytic processed and transported via sweat to the epidermal surface to act as peptide antibotic, but it is not induced under inflammation. We have established the role of DCD in melanoma growth and survival by silencing DCD expression in human melanoma G361 cell line and overexpression in murine melanoma B16 cell line. Downregulation of DCD in G-361 cell line significantly reduced cellular resistance to cytotoxic agents. Balb/c Nude mice inoculated with 1x106 G-361 cells underwent a progressive increase in the tumor size and body weight loss, whereas animals inoculated with G-361-IBC I melanoma cells expressing DCD shRNA, we observed a significant difference in tumor volumes. Moreover, administration of rabbit polyclonal antibody against DCD in mice bearing G361 xenografts for four weeks delayed tumor growth. To examine tumor heterogeneity we isolated by FACS cell sorting specific cancer-stem cell populations based on cell size and enhanced tumorigenic capacity in Nude mice. In parallel, we are employing the microarray and exome methodologies to define genes that are up- and downregulated, patterns of genetic modifications and gene mutation in specific oncogenic pathways to evaluate the hypothesis that DCD control multiple oncogenic stimuli (EGFR/HER2, C-MYC, PI3K/AKT/mTOR, VEGF, BRAF/RAS, etc.). We will summarize these results and highlight genetic and biological mechanisms suggesting that DCD functions as tumor growth and cell survival factor. Citation Format: Beatriz A. Sangiuliano, Marcela Nancy Perez, Aline Cadurin, Andrew Aguiar, Dayson F. Moreira, Jose E. Belizario. Role of Dermcidin in Tumorigenesis of Skin Cancers [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr A26.